Crystalline form of ANAVEX2-73 for the treatment of Alzheimer&#39;s disease

ABSTRACT

Composition and method for treatment of Alzheimer&#39;s disease that includes ANAVEX2-73. Method of treatment of Alzheimer&#39;s disease using pharmaceutical compositions comprising ANAVEX2-73 according to an intermittent dosage regimen.

FIELD

The present disclosure relates to pharmaceutical compounds andcompositions for the treatment of Alzheimer's disease. In particular,the present disclosure relates to the use of pharmaceutical compositionscomprising ANAVEX2-73 (also A2-73) for the treatment of Alzheimer'sdisease.

BACKGROUND

Despite major efforts aimed at finding a treatment for Alzheimer'sdisease, progress in developing compounds that can relieve cognitivedeficits associated with the disease has been slow. ANAVEX2-73 or A-273(tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride)is a compound which is believed to bind to sigma-1 and muscarinicacetylcholine receptors with affinities in the low micromolar range.ANAVEX2-73 has the chemical structure:

The sigma-1 receptor is a chaperone protein in the endoplasmic reticulum(ER) that chaperones the IP3 receptor at the ER and mitochondrioninterface to ensure proper Ca²⁺ signaling from the ER into themitochondrion. Under pathological conditions in which cells encounterstress that results in the ER losing its global Ca²⁺ homeostasis, thesigma-1 receptor translocates and counteracts the arising apoptosis. Asa result, the sigma-1 receptor is a receptor chaperone essential for themetabotropic receptor signaling and for the survival against cellularstress. See Centr. Nerv. Syst. Agents Med. Chem. 9(3), 184-189 (2009).

It has been reported that ANAVEX2-73 showed neuroprotective potentialagainst amyloid toxicity in mice. In particular, ANAVEX2-73 has beenreported as attenuating oxidative stress, caspases induction, cellularloss and learning and memory deficits observed in mice one week afterthe i.c.v. injection of an oligomeric preparation of amyloid β₂₅₋₃₅peptide (Aβ₂₅₋₃₅). See J. Psychopharmacol. 25(8), 1101-1117 (2011). Morerecently, it has been reported that ANAVEX2-73 blocked theAβ₂₅₋₃₅-induced P-Akt decrease and P-GSK-3β increase, indicatingactivation at the PI3K neuroprotective pathway. SeeNeuropsychopharmacology 38, 1706-1723 (2013). In the dose-range tested,ANAVEX2-73 attenuated the hyperphosphorylation of Tau on physiologicalepitopes (AT-8 antibody clone) and on pathological epitopes (AT-100clone). ANAVEX2-73 also has been reported to decrease theAβ₂₅₋₃₅-induced endogenous Aβ₁₋₄₂ seeding.

Reference is made to U.S. Patent Publication No. 2014/0296211 entitled“ANAVEX2-73 AND CERTAIN ANTICHOLINESTERASE INHIBITORS COMPOSITION ANDMETHOD FOR NEUROPROTECTION,” to Vamvakides et al., filed Jul. 12, 2013;U.S. Ser. No. 62/065,833 entitled “A19-144, A2-73 AND CERTAINANTICHOLINESTERASE INHIBITOR COMPOSITIONS AND METHOD FOR ANTI-SEIZURETHERAPY,” filed Oct. 20, 2014; U.S. Patent application entitled “CRYSTALFORMS OF TETRAHYDRO-N,N-DIMETHYL-2,2-DIPHENYL-3-FURANMETHANAMINEHYDROCHLORIDE, PROCESSES OF MAKING SUCH FORMS, AND THEIR PHARMACEUTICALCOMPOSITIONS” and filed on date even herewith; U.S. Patent applicationentitled “ENANTIOMERS OF A2-73, ANALOGUES, AND SIGMA AGONIST ACTIVITY”and filed on date even herewith. The teaching of these applications andpublications and all references cited herein are incorporated byreference in their entirety.

SUMMARY OF THE PRESENT DISCLOSURE

The present disclosure comprises a pharmaceutical composition for thetreatment of Alzheimer's disease comprising a therapeutically effectiveamount of ANAVEX2-73. Particular reference is made to treatment with thecomposition wherein the Alzheimer's disease is mild-to-moderate, andmore particularly wherein the ANAVEX2-73 is characterized by the PXRDpattern shown in FIG. 1 as well as characterized by thethermogravimetric analysis of FIG. 2a or FIG. 2b and characterized bythe differential scanning calorimetry analysis of FIG. 3a, 3b , or 3c.

Further included is the pharmaceutical composition wherein theANAVEX2-73 is characterized by the particle shapes or sizes as depictedin FIG. 4a , FIG. 4b , or FIG. 4c . Specific reference is made to aparticle size of between 1 and 50 μm.

Noted therapeutically effective amount of ANAVEX2-73 include about 1 mgto about 60 mg and particularly about 30 mg to about 50 mg. Furthernoted are therapeutically effective amounts of about 3 mg to about 5 mg,and particularly for intravenous administration. Oral dosage forms arenoted.

Yet further included are combination dosages comprising at least oneacetylcholinesterase inhibitor with particular reference to donepezil,galantamine, rivastigmine, or memantine.

The present disclosure contemplates a method of treating Alzheimer'sdisease in a subject comprising administering to the subject apharmaceutical compositions and combinations noted above.

Contemplated dosage regimens include administering to the subject apharmaceutical composition comprising ANAVEX2-73 according to anintermittent dosing regimen of at least two cycles, each cyclecomprising (a) a dosing period during which a therapeutically effectiveamount of said pharmaceutical composition is administered to saidpatient and, thereafter, (b) a resting period. In some embodiments thedosing period and the resting period are of the same duration or are ofdifferent durations.

Attention is brought to the dosing period and the resting period in therange of a lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14days to an upper limit of about 28 days, 27 days, 26 days, 25 days, 24days, 23 days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16days, 15 days, and 14 days. Also noted is the dosing period of betweenabout 1 day and 12 days and the resting period is between about 1 dayand 12 days with particular reference to a dosing period is 12 days andresting period is 12 days. Such regimen is usefully employed wherein thetherapeutically effective amount of said pharmaceutical composition ofANAVEX2-73 is about 1 mg to about 60 mg and particularly about 30 mg toabout 50 mg, and particularly for oral dosage forms. Also contemplatedare ANAVEX2-73 dosages of about 3 mg to about 5 mg and particularly withintravenous administration.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to describe the manner in which the advantages and features ofthe disclosure can be obtained, reference is made to embodiments thereofwhich are illustrated in the appended drawings. Understanding that thesedrawings depict only exemplary embodiments of the disclosure and are nottherefore to be considered to be limiting of its scope, the principlesherein are described and explained with additional specificity anddetail through the use of the accompanying drawings in which:

FIG. 1 depicts a powder X-ray diffraction (PXRD) pattern of ANAVEX2-73,according to an embodiment of the present disclosure;

FIG. 2a depicts a thermogravimetric analysis (TGA) of ANAVEX2-73,according to an embodiment of the present disclosure;

FIG. 2b depicts a thermogravimetric analysis (TGA) of ANAVEX2-73,according to an embodiment of the present disclosure;

FIG. 3a depicts differential scanning calorimetry (DSC) analysis datafor ANAVEX2-73, according to an embodiment of the present disclosure;

FIG. 3b depicts differential scanning calorimetry (DSC) analysis datafor ANAVEX2-73, according to an embodiment of the present disclosure;

FIG. 3c depicts differential scanning calorimetry (DSC) analysis datafor ANAVEX2-73, according to an embodiment of the present disclosure;

FIG. 4a depicts an SEM micrograph demonstrating the size and morphologyof the particles of ANAVEX2-73, according to an embodiment of thepresent disclosure;

FIG. 4b depicts an SEM micrograph demonstrating the size and morphologyof the particles of ANAVEX2-73, according to an embodiment of thepresent disclosure;

FIG. 4c depicts an SEM micrograph demonstrating the size and morphologyof the particles of ANAVEX2-73, according to an embodiment of thepresent disclosure;

FIG. 5 is a plot illustrating P300 ERP wave data for twelve patients atbaseline and day 36 following the on-off-on ANAVEX2-73 dosing regimen,as compared to a healthy control group;

FIG. 6 illustrates P300 amplitude data for twelve patients at baselineand day 36 following the on-off-on ANAVEX2-73 dosing regimen, ascompared to a healthy control group;

FIG. 7 illustrates P300 amplitude data for twelve patients at day 36 (1month) following the on-off-on ANAVEX2-73 dosing regimen, as compared tohistorical donepezil and control data;

FIG. 8 illustrates electroencephalographic (EEG) peak alpha frequency(PAF) data for twelve patients at baseline and day 36 following theon-off-on ANAVEX2-73 dosing regimen, as compared to a healthy controlgroup; and

FIG. 9 illustrates an electroencephalographic (EEG) power spectrumindicating the peak alpha frequency (PAF).

DETAILED DESCRIPTION

Various embodiments of the disclosure are discussed in detail below.While specific implementations are discussed, it should be understoodthat this is done for illustration purposes only. A person skilled inthe relevant art will recognize that other components and configurationsmay be used without parting from the spirit and scope of the disclosure.

It should be understood at the outset that although illustrativeimplementations of one or more embodiments are illustrated below, thedisclosed method may be implemented using any number of techniques. Thedisclosure should in no way be limited to the illustrativeimplementations, drawings, and techniques illustrated herein, but may bemodified within the scope of the appended claims along with their fullscope of equivalents.

In the following discussion and in the claims, the terms “including” and“comprising” are used in an open-ended fashion, and thus should beinterpreted to mean “including, but not limited to . . . ”. The variouscharacteristics described in more detail below, will be readily apparentto those skilled in the art with the aid of this disclosure upon readingthe following detailed description, and by referring to the accompanyingdrawings.

The present disclosure generally relates to pharmaceutical compounds andcompositions for the treatment of Alzheimer's disease. Moreparticularly, the present disclosure relates to the use ofpharmaceutical compositions containing ANAVEX2-73 for the treatment ofAlzheimer's disease.

According to an embodiment of the present disclosure, ANAVEX2-73 can beproduced by charging a solution oftetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine free base inethyl acetate with isopropanol. The ethylacetate is removed bydistillation and the remaining isopropanol solution containingtetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine free base isclear filtered. Aqueous hydrochloric acid (1.1 eq) is charged to theisopropanol solution and the formed crystalline HCl salt oftetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine,tetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride(ANAVEX2-73), is isolated by filtration and dried under vacuum at 55° C.for 3 days. The ANAVEX 2-73, thus obtained, is characterized by powderX-ray diffraction (PXRD), thermogravimetric analysis (TGA), differentialscanning calorimetry (DSC), and scanning electron microscopy (SEM), asshown in FIGS. 1-4.

FIG. 1 depicts a powder X-ray diffraction (PXRD) pattern for ANAVEX2-73,according an embodiment of the present disclosure. The PXRD patternshown in FIG. 1 was collected using a Siemens D5000 powderdiffractometer with CuKα radiation (1.54056 Å). The tube voltage andamperage were set at 40 kV and 40 mA, respectively. The divergence slitand antiscattering slit settings were variable for the illumination onthe 20 mm sample area. Each sample was scanned between 5° and 40° in 2θwith a step size of 0.02°. The measurement time per step was 2 seconds.The instrument was previously calibrated using a silicon standard. Asshown in FIG. 1, the PXRD indicates that the ANAVEX2-73 material ishighly crystalline with several characteristic peaks in the 10-20° 2θrange.

FIGS. 2a and 2b depict thermogravimetric analysis (TGA) data forANAVEX2-73, according to an embodiment of the present disclosure. Theweight loss of the sample as a function of temperature was measuredusing the Thermal Advantage TGA Q5000IR (TA instrument) module. Thesamples (˜7.8 mg) was placed onto the platinum pan (100 μL) and heatedfrom 25°-350° at a heating rate of 10° C./min under nitrogen purge. Asshown in FIGS. 2a-2b , the TGA (and derivative of weight change) curvesindicate that the minor weight change at around 80° C. followed bycontinuous weight loss from 150° C. with two major steps (first one with˜29% at 228° C.) up to 275° C. The initial weight loss could beattributed to the evaporation of adsorbed water or solvent ofcrystallization and the latter weight changes may be attributed to thedegradation of impure solid phases (or impurities) followed by amelt-degradation of ANAVEX2-73.

FIGS. 3a, 3b, and 3c depict differential scanning calorimetry (DSC) datafor ANAVEX2-73, according to an embodiment of the present disclosure.The thermal behavior of ANAVEX2-73 was studied using a Thermal AdvantageDSC Q1000 (TA instruments) equipped with a refrigerated cooling system.The instrument had been calibrated for temperature and enthalpy usingindium. 1-2 mg of the sample was accurately weighed into a non-hermeticaluminum pan and crimped. The sample was scanned from 25° C. to 275° C.at a heating rate of 10° C./min under continuous nitrogen purge (50mL/min). As shown in FIGS. 3a-3c , the DSC thermograms indicateendothermic events with onset at ˜80° C. (minor) and 115° C. (broad)followed by an exothermic peak and a sharp endothermic event with onsetat 227° C. DSC analysis seemed to be in agreement with the TGA analysissuggesting that the compound was undergoing melt-degradation. However,start of the degradation of the main phase in the vicinity but beforethe melting is also possible.

FIGS. 4a, 4b, and 4c depict scanning electron microscope (SEM)micrographs demonstrating the size and morphology of the particles ofANAVEX2-73, according to an embodiment of the present disclosure. Thesize and morphology of the particles was studied using a Philips XL30(The Netherlands) scanning electron microscope (SEM). The samples weresprinkled onto double-sided tape that had been secured onto an aluminumstub and then gold sputter-coated at mA for 40 seconds under an argonatmosphere. The particles were analyzed at suitable accelerationvoltages and magnifications. Representative micrographs were taken andthe particle size was estimated. The SEM micrographs demonstrated thatANAVEX2-73 is primarily comprised of aggregated crystals (prisms toblocks) with a primary particle size distribution between 1 and 50 μm.

The safety of ANAVEX2-73 has been demonstrated in a randomized,placebo-controlled single ascending dose Phase 1 study of ANAVEX2-73 in22 healthy male volunteers. See Poster: A Phase 1 Dose Escalation Studyto Investigate Safety, Tolerability, and Pharmacokinetics of ANAVEX2-73in Healthy Male Subjects, CNS Summit 2014, Boca Raton, Fla., by OleVoges, Ingo Weigmann, Norman Bitterlich, Christoph Schindler andChristopher Missling. Ascending single oral doses of 1 mg, 10 mg, 30 mg,40 mg, 50 mg, and 55 mg of ANAVEX2-73 were safe and well tolerated inhealthy subjects. No serious adverse events occurred. Based on thefrequency and intensity of non-treatment emergent adverse events (TEAEs)the maximum tolerable dose (MTD) and the minimum intolerable dose (MID)were defined as 55 mg and 60 mg, respectively. A highest doses, observedadverse events included moderate and reversible dizziness and headache,common in drugs that target the central nervous system. Blood pressureand resting heart rate and other clinical parameters such as vital signsand 12-lead electrocardiogram (ECG) did not show any clinically relevantor dose-dependent changes. The QT interval and QTcB also did not revealany clinically significant changes. The pharmacokinetics of ANAVEX2-73was found to be suitable for daily oral dosing.

The efficacy of ANAVEX2-73 polymorph for the treatment of Alzheimer'sdisease has been demonstrated by initial clinical data from an on-goingPhase 2a clinical trial. The 36-day multicenter randomized clinicaltrial included both male and female mild-to-moderate Alzheimer's diseasepatients. ANAVEX2-73 was administered to twelve subjects as an add-ontherapy to the donepezil current standard of care. ANAVEX2-73 wasadministered according to a two-period on-off-on cross-over dosingregimen in which the subjects were administered ANAVEX2-73 for 12 days(1^(st) period) followed by a 12-day wash-out period before beingadministered ANAVEX2-73 for a second 12-day period (2^(nd) period).Those subjects that were administered ANAVEX2-73 by oral administrationduring the 1^(st) period were administered ANAVEX2-73 intravenouslyduring the 2^(nd) period, and vice versa. About half of the subjectswere administered a 30 mg oral dosage form while the other half ofsubjects were administered a 50 mg oral dosage form. The intravenousdosage was either 3 mg or 5 mg, with about half of the subjectsadministered 3 mg and the other half administered 5 mg.

Resting electroencephalographic (EEG) activity and event relatedpotentials (EEG/ERP) were used to assess the cognitive effects ofANAVEX2-73 administration. Event related potentials (ERPs) are voltagechanges time-locked to some physical or mental occurrence in ongoingelectrical brain activity, as recorded by EEG. Event-related potentials(ERPs) provide a sensitive and reliable measure of the cognitive effectsassociated with early Alzheimer's disease. ERPs reflect wellcharacterized brain responses to sensor, motor and cognitive events andhave been found to be altered in Alzheimer disease patients beginning inthe very early stages of the disease. See for example, New Encycl.Neurosci., Oxford Academic Press, p. 13-18 (2009). For example, ERPtests on young presymptomatic individuals who carry mutations in thepresenilin-1 and amyloid precursor protein genes show significantchanges in ERP patterns years before the onset of behavioral symptomsand the development of Alzheimer's disease. See for example, Neurology73, 1649-1655 (2009); Neurology 77, 469-475 (2011). ERPs have also beenshown to reliably track the cognitive decline associated withAlzheimer's disease progression. For instance, ERP markers of cognitivefunction are increasingly altered in longitudinal studies on individualswith mild cognitive impairment (MCI) and Alzheimer's disease patients.See for example, Clin. Neurophysiol. 122, 1322-1326 (2011); Clin.Neurophysiol. 121, 194-199 (2010). Additionally, ERPs have been shown tobe sensitive to the effects of cognitive enhancers currently used forthe treatment of Alzheimer's disease. For example, ERP measures havebeen demonstrated to be reliable instruments for the assessment of thecognitive response to cholinesterase inhibitors, such as donepezil, andthe effects of the selective NMDA antagonist memantine, as measured byERPs, have been shown to correlate with changes in the Mini Mental StateExamination (MMSE) score. See for example, Neurol. Neurochir. Pol. 35Suppl 3, 37-43 (2001); Clin. Neuropharmacol. 25, 207-215 (2002);Neurosci. Biomed. Eng. 1, 34-39 (2013).

In particular, the auditory P300 component of the ERP has been widelyapplied in the study of age-related cognitive dysfunction because it isthought to reflect attentional and memory processes. Auditory P300 is apositive deflection occurring at about 300 ms from stimulus onset. It isgenerated by the activation of multiple neocortical and limbic regions.Auditory P300 has two functionally different components, an earlier P3acomponent that is maximal over frontocentral regions, and a later P3bcomponent (hereafter “P300”) that is maximal at the posterior scalplocations. See for example, Int. J. of Alzheimer's Dis. 2011, Article ID653173, 1-7 (2011). P300 amplitude data collected as part of a doubleblind six month study for 15 patients with mild Alzheimer's disease ondonepezil, as compared to a vitamin E baseline, has shown that P300amplitude data correlates with ADAS-Cog and MMSE data for the samepatients. See, Clin. Neuropharmacol. 25(4), 207-215 (2002).

Subjects were tested using a three-stimulus oddball paradigm. Stimulicomprised of standard tones (1000 Hz), target tones (2000 Hz) andunexpected distractor tones (white noise) that were played withprobabilities of 0.75, 0.15, and 0.10. Tones were presented inpseudorandom order, so that target and distractor tones were neverpresented sequentially. Subjects were instructed to respond to thetarget stimuli by pressing a button with their dominant hand. For eachtest, between 300 and 400 stimuli were presented binaurally throughinsert ear phones at 70 dB volume. The tone duration for each stimuluswas 100 ms with rise and fall times of 10 ms. The interstimulus intervalwas randomized between 1.5 and 2 s. Electroencephalographic (EEG)activity was recorded from seven electrode sites (Fz, Cz, Pz, F3, P3,F4, and P4) of the international 10-20 system using a COGNISION™ Headset(Neuronetrix). Electrodes were referenced to averaged mastoids (M1, M2)and Fpz served as the common electrode. The headset used for datacollection had been validated to perform reliable ERP recordings whenskin contact impedance was below 70 kΩ. Impedance was automaticallychecked at all electrodes after each target or distractor tone, and waskept below this limit throughout each test. Data was collected from −240to 1,000 ms around the stimuli, digitized at 125 Hz, and bandpassfiltered from 0.3 to 35 Hz. An automatic artifact threshold detectionlimit of ±100 μV was set for the tests. Trial sets of a deviant tone andthe immediately preceding standard tones (epoch sets) with artifactsexceeding the threshold were rejected in real time and immediatelyrepeated.

FIG. 5 illustrates P300 ERP wave data for twelve patients at baselineand day 36 following the on-off-on ANAVEX2-73 dosing regimen, withoutany dose optimization. FIG. 5 also illustrates data for a healthycontrol group obtained from a manuscript that was recently submitted byCecchi et al. to the journal Alzheimer's & Dementia. The P300 ERP wavedata indicates that administration of ANAVEX2-73 improved measuredcognitive performance as compared to the baseline data. Additionally,the P300 ERP wave plot for subjects undergoing the ANAVEX2-73 dosageregimen more closely resembled the P300 ERP wave plot obtained forhealthy subjects.

FIG. 6 illustrates P300 amplitude data for twelve patients at baselineand day 36 following the on-off-on ANAVEX2-73 dosing regimen, ascompared to the healthy control group. The same data is provided inTable 1. As shown in Table 1, the P300 amplitude for subjects undergoingthe ANAVEX2-73 dosage regimen increased by 38% as compared to thebaseline P300 amplitude. Additionally, the P300 amplitude for subjectsundergoing the ANAVEX2-73 dosage regimen more closely resembled the P300amplitude data obtained for the healthy control group than the baselineP300 amplitude data.

TABLE 1 Percentage Increase P300 Amplitude (mV) Over Baseline DataBaseline 4.85  0% Day 36 6.69 38% Healthy Ctrl 7.36

Table 2 demonstrates the effects of the ANAVEX2-73 dosage regimen on thecognitive performance of the twelve subjects at baseline and day 36following the on-off-on ANAVEX2-73 dosing regimen, as measured by thetarget detection task of the ERP test. Table 2 also provides targetdetection task data for the healthy control group. As shown in Table 2,the button press accuracy was improved for subjects undergoing theANAVEX2-73 dosage regimen as compared to the baseline. Additionally, themedian reaction time and the false alarm percentage was reduced for theANAVEX2-73 administered subjects as compared to the baseline. Thehealthy control group out-performed the day 36 ANAVEX2-73 subjects inbutton press accuracy and median reaction time. However, the day 36ANAVEX2-73 subjects out-performed the healthy control group in falsealarm percentage. The data provided in Table 2 indicates that ANAVEX2-73administration improves both the accuracy and the reaction time ofsubjects performing the target detection task of the ERP test.

TABLE 2 Target Detection Task Baseline Day 36 Healthy Control ButtonPress 86.2 ± 4.47 87.5 ± 4.01 94.1 ± 1.10 Accuracy (%) False Alarms 2.67± 1.12 0.64 ± 0.26 1.10 ± 0.20 (%) Median Reaction  593 ± 33.0  534 ±42.0  458 ± 11.4 Time (ms)

FIG. 7 illustrates P300 amplitude data for twelve patients at day 36 (1month) following the on-off-on ANAVEX2-73 dosing regimen, as compared tohistorical donepezil and control data obtained from Clin.Neuropharmacol. 25(4), 207-215 (2002). As shown in FIG. 7, the measuredP300 amplitude change for subjects undergoing the ANAVEX2-73 dosageregimen, as compared to the baseline P300 amplitude, is about four timeshigher than the P300 amplitude change observed in historical data forpatients administered donepezil at the 1 month time point. Further, thepercent P300 amplitude change after 1 month is greater than the percentP300 amplitude change observed in historical data for patientsadministered donepezil after 6 months. The data shown in FIG. 7 suggeststhat administration of ANAVEX2-73 increases measured P300 amplitude forsubjects at an earlier time point in the dosage regimen and to a greaterdegree than administration of donepezil.

FIG. 8 illustrates electroencephalographic (EEG) peak alpha frequency(PAF) data for twelve patients at baseline and day 36 following theon-off-on ANAVEX2-73 dosing regimen, as compared to a healthy controlgroup. Electroencephalographic (EEG) peak alpha frequency (PAF),measured in Hz, is a distinctive individual “fingerprint” that has beencorrelated to cognitive performance and reflects a trait or state ofcognitive preparedness. Patients with Alzheimer's disease have beenfound to have reduced PAF when compared to age-matched controls. PAFmeasures the discrete frequency with the highest magnitude within thealpha range. For example, FIG. 9 illustrates an electroencephalographic(EEG) power spectrum indicating the peak alpha frequency (PAF). As shownin FIG. 8, the measured PAF for subjects undergoing the ANAVEX2-73dosage regimen was higher than the baseline measurement of PAF. FIG. 8indicates that ANAVEX2-73 is able to shift PAF in subjects as comparedto the measured PAF baseline. In addition, ANAVEX2-73 was found toimprove the P300 signal in 10 out of the 12 patients (83%) studied.

The results for the twelve subject on-off-on dosing regimen ofANAVEX2-73, shown in FIGS. 5-9, were achieved without any doseoptimization. Preliminary measured Mini Mental State Examination (MMSE)and Cogstate scale changes are consistent with the observed trend of thecognitive EEG/ERP effect. The safety profile of ANAVEX2-73 during Phase2a trials appears consistent with the Phase 1 data. An additional 20subjects will be studied during the remainder of the Phase 2a clinicaltrial. Phase 2b clinical trials, involving an additional 26-weekextension of daily oral dosage administration of ANAVEX2-73 is on-going.

According to the present disclosure, ANAVEX2-73 can be administeredaccording to an intermittent dosing schedule, in which a subject isadministered ANAVEX2-73 for a period of days, followed by a period ofdays in which no ANAVEX2-73 is administered, before administration ofANAVEX2-73 is once again resumed. In some cases, the period ofadministration is of the same duration as the period of noadministration. In other cases, the period of administration may be of alonger or shorter duration than the period of administration. In somecases, ANAVEX2-73 is administered according to an intermittent dosingregimen of at least two cycles, each cycle comprising (a) a dosingperiod during which a therapeutically effective amount of ANAVEX2-73 isadministered to a patient and thereafter (b) a resting period. In oneembodiment, the dosing period is for 1-12 days and the rest period isfor 1-12 days. In other embodiments, the dosing period can be 1 day, 2days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days,11 days, 12 days, 13 days, or 14 days. In some embodiments, the restingperiod can be 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days.

In some cases, the dosing period described herein can be in the range ofa lower limit of about 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, and 14 days toan upper limit of about 28 days, 27 days, 26 days, 25 days, 24 days, 23days, 22 days, 21 days, 20 days, 19, days, 18 days, 17 days, 16 days, 15days, and 14 days. In some cases, the resting period described hereincan be in the range of a lower limit of about 1 day, 2 days, 3 days, 4days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days,13 days, and 14 days to an upper limit of about 28 days, 27 days, 26days, 25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19, days, 18days, 17 days, 16 days, 15 days, and 14 days.

In one embodiment, the intermittent dosage schedule described hereincomprises an oral dosage form comprising about 30 mg ANAVEX2-73. Inanother embodiment, the intermittent dosage schedule described hereincomprises an oral dosage form comprising about 50 mg ANAVEX2-73. Inanother embodiment, the intermittent dosage schedule described hereincomprises an oral dosage form comprising between about 30 mg and 50 mgANAVEX2-73. In another embodiment, the intermittent dosage scheduledescribed herein comprises an oral dosage form comprising between about1 mg and 55 mg ANAVEX2-73.

In some cases the oral dosage form described herein can be in the rangeof a lower limit of about 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, and 30mg ANAVEX2-73 to an upper limit of about 60 mg, 55 mg, 50 mg, 45 mg, 40mg, 35 mg, and 30 mg ANAVEX2-73.

In one embodiment, the intermittent dosage schedule described hereincomprises intravenous administration of about 3 mg ANAVEX2-73. Inanother embodiment, the intermittent dosage schedule described hereincomprises intravenous administration of about 5 mg ANAVEX2-73. Inanother embodiment, the intermittent dosage schedule described hereincomprises intravenous administration of between about 3 mg and 5 mgANAVEX2-73. In another embodiment, the intermittent dosage scheduledescribed herein comprises intravenous administration of between about 1mg and 10 mg ANAVEX2-73. In some cases the intravenous administrationdescribed herein can be in the range of a lower limit of about 1 mg, 2mg, 3 mg, 4 mg, and 5 mg ANAVEX2-73 to an upper limit of about 10 mg, 9mg, 8 mg, 7 mg, 6 mg, and 5 mg ANAVEX2-73.

All numbers and ranges disclosed above may vary by some amount. Whenevera numerical range with a lower limit and an upper limit is disclosed,any number and any included range falling within the range isspecifically disclosed. In particular, every range of values (of theform, “from about a to about b,” or equivalently, “from approximately ato b,” or, equivalently, “from approximately a-b”) disclosed herein isto be understood to set forth every number and range encompassed withinthe broader range of values.

The compositions disclosed herein individually or in combination areemployed in admixture with conventional excipients, i.e.,pharmaceutically acceptable organic or inorganic carrier substancessuitable for parenteral, enteral (e.g., oral or inhalation) or topicalapplication which do not deleteriously react with the activecompositions. Suitable pharmaceutically acceptable carriers include butare not limited to water, salt solutions, alcohols, gum arabic,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, titanium dioxide, silicic acid, viscous paraffin, perfume oil,fatty acid esters, hydroxyl methylcellulose, polyvinyl pyrrolidone, etc.The pharmaceutical preparations can be sterilized and if desired mixedwith auxiliary agents, e.g., lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, flavoring and/or aromatic substances and the likewhich do not deleteriously react with active compositions. They can alsobe combined where desired with other active agents, e.g., vitamins.

In some embodiments, dosage forms include instructions for the use ofsuch compositions. For parenteral application, particularly areinjectable, sterile solutions, preferably oily or aqueous solutions, aswell as suspensions, emulsions, or implants, including suppositories.Ampules, vials, and injector cartridges are convenient unit dosages.“Unit dosage form” shall mean single administration entity. By way ofexample, a single tablet, capsule, dragee, or trochee, suppository, orsyringe.

Also for parenteral application, particularly suitable are tablets,dragees, liquids, drops, suppositories, or capsules. A syrup, elixir, orthe like can be used wherein a sweetened vehicle is employed. Sublingualand buccal forms are also noted.

Sustained or direct release compositions can be formulated, e.g.,liposomes or those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc. It is also possible to freeze-dry the newcompositions and use the lyophilizates obtained, for example, for thepreparation of products for injection.

EXAMPLES

The following examples show uses of ANAVEX2-73 in the treatment ofpatients with Alzheimer's disease or presenting with the early signs ofAlzheimer's disease. The clinical determination that a patient may haveAlzheimer's disease or is presenting with early signs of Alzheimer'sdisease is well known in the art. By way of example, the followingreferences (and all publications cited herein) are incorporated byreference herein in their entireties: Dementia: From Diagnosis toManagement—A Functional Approach 1^(st) Edition, Psychology Press (Feb.17, 2009); Clinician's Guide to Psychological Assessment and Testing:With Forms and Templates for Effective Practice 1^(st) Edition, SpringerPublishing Company (Sep. 18, 2012); Neurodegener. Dis. Manag. 5(3),191-201 (2015); Artif. Intell. Med. 64(1), 59-74 (2015); Clin. Chem.60(12), 1585-1586 (2014); and Metabolism 64(3 Suppl 1), S47-50 (2014).

Example 1

A 63 year-old male presents with early signs of Alzheimer's disease. Heis orally administered a pharmaceutical composition containing 30 mgANAVEX2-73 according to an intermittent dosing regimen where each cycleincludes daily administration for 10 days (dosing period) followed by 10days of no administration (resting period). The patient is administered30 mg ANAVEX2-73 according to the intermittent dosing regimen for 6months. His loss of cognitive function stabilizes during that period.

Example 2

A 58 year-old male presents with signs of early onset Alzheimer'sdisease. He is orally administered a pharmaceutical compositioncontaining 50 mg ANAVEX2-73 according to an intermittent dosing regimenwhere each cycle includes daily administration for 10 days (dosingperiod) followed by 20 days of no administration (resting period). Hisloss of cognitive function stabilizes during that period.

Example 3

A 60 year-old female presents with signs of early onset Alzheimer'sdisease. She is administered 3 mg of ANAVEX2-73 intravenously accordingto an intermittent dosing regimen where each cycle includes dailyadministration for 5 days (dosing period) followed by 20 days of noadministration (resting period) for one year. Her loss of cognitivefunction stabilizes during that period.

Example 4

A 55 year-old male presents with signs of early onset Alzheimer'sdisease. He is administered 5 mg of ANAVEX2-73 intravenously accordingto an intermittent dosing regimen where each cycle includes dailyadministration for 14 days (dosing period) followed by 7 days of noadministration (resting period) for one year. His loss of cognitivefunction stabilizes during that period.

Example 5

A 64 year-old female presents with early signs of Alzheimer's disease.She is orally administered a pharmaceutical composition containing 50 mgANAVEX2-73 according to an intermittent dosing regimen where each cycleincludes daily administration for 14 days (dosing period) followed by 7days of no administration (resting period). The patient is administered50 mg ANAVEX2-73 according to the intermittent dosing regimen for 6months. Her loss of cognitive function is stabilized during that period.

What is claimed is:
 1. A pharmaceutical composition for the treatment ofAlzheimer's disease comprising a therapeutically effective amount oftetrahydro-N,N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride(ANAVEX2-73), wherein the ANAVEX2-73 is a crystalline form of Anavex2-73characterized by the powder X-ray diffraction (PXRD) pattern shown inFIG.
 1. 2. The pharmaceutical composition according to claim 1, whereinthe Alzheimer's disease is mild-to-moderate Alzheimer's disease.
 3. Thepharmaceutical composition according to claim 1, wherein the crystallineform of ANAVEX2-73 is characterized by the thermogravimetric analysis ofFIG. 2a or FIG. 2 b.
 4. The pharmaceutical composition according toclaim 1, wherein the crystalline form of ANAVEX2-73 is characterized bythe differential scanning calorimetry analysis of FIG. 3a, 3b , or 3 c.5. The pharmaceutical composition according to claim 1, wherein thecrystalline form of ANAVEX2-73 is characterized by the particle shapesas depicted in FIG. 4a , FIG. 4b , or FIG. 4 c.
 6. The pharmaceuticalcomposition according to claim 1, wherein the crystalline form ofANAVEX2-73 is characterized by the particle sizes as depicted in FIG. 4a, FIG. 4b , or FIG. 4 c.
 7. The pharmaceutical composition according toclaim 1, wherein the crystalline form of ANAVEX2-73 is characterized bya particle size of between 1 and 50 μm.
 8. The pharmaceuticalcomposition according to claim 1, wherein the therapeutically effectiveamount is about 1 mg to about 60 mg.
 9. The pharmaceutical compositionaccording to claim 1, wherein the therapeutically effective amount isabout 30 mg to about 50 mg in an oral dosage form.
 10. Thepharmaceutical composition according to claim 1, wherein thetherapeutically effective amount is about 3 mg to about 5 mg in anintravenous dosage form.
 11. The pharmaceutical composition according toclaim 1, further comprising at least one acetylcholinesterase inhibitor.12. The pharmaceutical composition according to claim 1, wherein the atleast one acetylcholinesterase inhibitor is selected from the groupconsisting of donepezil, galantamine, rivastigmine, or memantine.
 13. Amethod of treating Alzheimer's disease in a subject comprisingadministering to the subject a therapeutically effective amount of apharmaceutical composition according to claim 1; and wherein saidpharmaceutical composition is administered according to an intermittentdosing regimen of at least two cycles, each cycle comprising (a) adosing period during which a therapeutically effective amount of saidpharmaceutical composition is administered to said patient and,thereafter, (b) a resting period.
 14. The method according to claim 13,wherein the dosing period and the resting period are of the sameduration.
 15. The method according to claim 13, wherein the dosingperiod and the resting period are of different durations.
 16. The methodaccording to claim 13, wherein the dosing period and the resting periodis in the range of a lower limit of about 10 days, 11 days, 12 days, 13days, and 14 days to an upper limit of about 28 days, 27 days, 26 days,25 days, 24 days, 23 days, 22 days, 21 days, 20 days, 19 days, 18 days,17 days, 16 days, 15 days, and 14 days.
 17. The method according toclaim 13, wherein the dosing period is 12 days and the resting period is12 days.
 18. The method according to claim 13, wherein thetherapeutically effective amount of said pharmaceutical composition isabout 1 mg to about 60 mg.
 19. The method according to claim 13, whereinthe therapeutically effective amount of said pharmaceutical compositionis about 30 mg to about 50 mg in an oral dosage form.
 20. The methodaccording to claim 13, wherein the therapeutically effective amount ofsaid pharmaceutical composition is about 3 mg to about 5 mg in anintravenous dosage form.
 21. The method according to claim 13, whereinthe pharmaceutical composition is administered daily.
 22. The methodaccording to claim 17, wherein the pharmaceutical composition isadministered for a period of at least 26 weeks.
 23. The method accordingto claim 17, wherein the therapeutically effective amount of saidpharmaceutical composition is about 1 mg to about 60 mg.
 24. The methodaccording to claim 17, wherein the therapeutically effective amount ofsaid pharmaceutical composition is about 30 mg to about 50 mg in an oraldosage form.
 25. The method according to claim 17, wherein thetherapeutically effective amount of said pharmaceutical composition isabout 3 mg to about 5 mg in an intravenous dosage form.